High-potency ligands for DREADD imaging and activation in rodents and monkeys

Jordi Bonaventura, Mark A.G. Eldridge, Feng Hu, Juan L. Gomez, Marta Sanchez-Soto, Ara M. Abramyan, Sherry Lam, Matthew A. Boehm, Christina Ruiz, Mitchell R. Farrell, Andrea Moreno, Islam Mustafa Galal Faress, Niels Andersen, John Y. Lin, Ruin Moaddel, Patrick J. Morris, Lei Shi, David R. Sibley, Stephen V. Mahler, Sadegh NabaviMartin G. Pomper, Antonello Bonci, Andrew G. Horti, Barry J. Richmond, Michael Michaelides

Research output: Contribution to journalArticlepeer-review

Abstract

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for human applications as well. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine, making it difficult to apply in basic and translational applications. Here we report the development of two novel DREADD agonists, JHU37152 and JHU37160, and the first dedicated 18F positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. We show that JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons, and at their long-range projections, enabling noninvasive and longitudinal neuronal projection mapping.

Original languageEnglish (US)
Article number4627
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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